Drug abuse in the U.S. in the 1980's increased concomitantly with the spread of AIDS. It has been suggested that physiological alterations associated with drug abuse predisposes the drug abuse population to increased susceptibility to HIV and contributes to the pathogenesis of AIDS. While the number of cases of tuberculosis in humans had decreased steadily since 1953, this trend has reversed dramatically since 1986. The resurgence of this highly virulent disease is largely related to the AIDS epidemic and is especially problematic in AIDS patients who are drug abusers. The goal is to investigate the association between drug abuse and infectious disease, particularly pulmonary infection, and to establish the molecular and cellular basis of this interaction. In the past three years, the team of investigators have developed an animal [swine] model to study the effect of drugs of abuse on human disease. The model evaluates of the effects of drugs of abuse on clinically- relevant diseases while it avoids the confounding difficulties of multiple drug abuse, and poor hygiene and nutrition. As an animal model for the study of human respiratory pathogens, several swine diseases parallel human disease. Suid-herpesvirus-1 (SHV-1) produces a respiratory disease similar to that of herpes simplex virus pneumonia in humans and Mycobacterium bovis affects swine as well as humans and is one of the infectious organisms which causes tuberculosis. The hypothesis is that under conditions of chronic opiate use, impaired immune function of the lung, particularly involving pulmonary macrophages, results in an attenuation of the immune system's ability to fight off bacterial invaders. Furthermore, the hypothesis extends that the mechanism of opiate immunosuppression involves modulation of cytokine gene expression. The first phase of studies will examine the effect of chronic morphine treatment on primary herpesvirus-induced and secondary Pasteurella multocida-induced pneumonia. The second phase of studies will focus on Mycobacterial infection, both primary virus-induced and Mycobacterium bovis alone. The first phase builds on work completed as part of a previous NIDA contract and focuses on putative mechanisms of suppression. The second phase extend investigations to an infection of critical importance to the drug abusing population and specifically to those infected with HIV.